RESEARCH ARTICLE SUMMARY
◥NEUROSCIENCE
Cerebellar modulation of the reward
circuitry and social behavior
Ilaria Carta, Christopher H. Chen,AmandaL.Schott,
Schnaude Dorizan, Kamran Khodakhah†
INTRODUCTION:Although the cerebellum
has long been considered to be a purely motor
structure, recent studies have revealed that it
also has critical nonmotor functions. Cerebel-
lar dysfunction is implicated in addictive be-
havior and in mental disorders such as autism
spectrum disorder (ASD), cognitive affective
syndrome, and schizophrenia. The cerebellum
is well poised to contribute to behavior be-
cause it receives a wide array of cortical and
sensory information and is subject to control
by a number of neuromodulators. To perform
its function, the cerebellum is believed to in-
tegrate these diverse inputs to provide the rest
of the brain with predictions required for opti-
mal behavior. Although there are many path-
waysforthistooccurinthemotordomain,
fewer exist for the nonmotor domain.RATIONALE:There are no direct pathways
emanating from the cerebellum that have been
shown to serve nonmotor functions. We hypoth-
esized that the cerebellum may contribute to
motivated behavior by a direct projection to
the ventral tegmental area (VTA), a structure
that is critical for the perception of reward
and control of social behaviors. Such a pro-
jection would explain why functional imag-
ing experiments indicate that the cerebellum
plays a role in addiction and would provideone potential mechanism by which cerebellar
dysfunction might contribute to the symptoms
of mental disorders.RESULTS:In mice, we found that mono-
synaptic excitatory projections from the cere-
bellar nuclei to the VTA powerfully activate
the reward circuitry and contribute to social
behavior. Using anatomical tracing, we showed
that axonal projections from the cerebellar
nuclei form synapses with both dopaminergic
and nondopaminergic neurons in the VTA. The
cerebello-VTA (Cb-VTA)
projections were power-
ful and their optogenetic
stimulation robustly in-
creased the activity of VTA
neurons both in vivo and
in vitro. Behavioral tests to
examine reward processing showed that stimu-
lation of the Cb-VTA projections was sufficient
to cause short-term and long-term place prefer-
ence, thereby demonstrating that the pathway
was rewarding. Although optogenetic inhibition
of Cb-VTA projections was not aversive, it com-
pletely abolished social preference in the three-
chamber test for sociability, which suggests that
the cerebellar input to the VTA is required for
normal social behavior. A role for the cerebellum
in social behavior was also indicated by corre-
lation between calcium activity in these axons
and performance in the three-chamber test. How-
ever, optogenetic activation of the Cb-VTA
inputs was not prosocial, hence the pathway
was not sufficient for social behavior.CONCLUSION:The Cb-VTA pathway de-
scribed here is a monosynaptic projection from
thecerebellumtoastructureknownprimarily
for its nonmotor functions. Our data support
a role for the cerebellum in reward process-
ing and in control of social behavior. We pro-
pose that this Cb-VTA pathway may explain,
at least in part, the association between the
cerebellum and addictive behaviors, and pro-
vides a basis for a role for the cerebellum in
other motivated and social behaviors. In ad-
dition to contributing to reward processing,
the VTA also targets a number of other brain
regions, such as the prefrontal cortex, that in
turn sustain a large repertoire of motor and
nonmotor behaviors. Direct cerebellar inner-
vation of the VTA provides a pathway by which
the cerebellum may modulate these diverse be-
haviors. The Cb-VTA pathway delineated here
provides a mechanism by which cerebellar dys-
function, by adversely affecting the VTA and its
targets, might contribute to mental disorders
such as ASD and schizophrenia.
▪RESEARCH
Cartaet al.,Science 363 , 248 (2019) 18 January 2019 1of1
The list of author affiliations is available in the full article online.
*These authors contributed equally to this work.
†Corresponding author. Email: [email protected]
Cite this article as I. Cartaet al.,Science 363 ,eaav0581(2019).
DOI: 10.1126/science.aav0581The cerebellum sends direct excitatory projections to the ventral tegmental area
(Cb-VTA).These projections likely play a role in reward processing and addictive behavior,
are required (but not sufficient) for social behavior, and may constitute one of the major
pathways by which cerebellar dysfunction contributes to mental disorders.
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